Idiopathic Pulmonary Fibrosis

June 9, 2014

Boehringer Ingelheim reported results
of two phase III trials of nintedanib for
idiopathic pulmonary fibrosis (IPF). The
double-blind, randomized and placebo-controlled
trials evaluated the effect of oral
nintedanib 150mg twice daily, on annual
rate of decline in forced vital capacity (FVC),
in people with IPF over 52 weeks. A total of
1,061 (n=638, nintedanib v. 423, placebo)
people with IPF were enrolled in the two
trials. In these trials, nintedanib reduced
the annual rate of FVC decline compared
to placebo by 48% in INPULSIS-1 (-114.7 v.
-239.9mL/year, respectively [95% CI: 77.7,
172.8]) and by 55% in INPULSIS-2 (-113.6 v.
-207.3 mL/year, respectively [95% CI: 44.8,
142.7]). The absolute change from baseline
in FVC at 52 weeks, a pre-specified secondary
endpoint, for nintedanib v. placebo
was 109.9 mL in INPULSIS-1 (-95.1 mL,
nintedanib vs. -205.0 mL, placebo [95% CI:
71.3, 148.6]) and 109.8 mL in INPULSIS-2
(-95.3 mL, nintedanib vs. -205.0 mL, placebo
[95% CI: 70.9, 148.6]). In both trials, the most
prevalent adverse events (AE) were gastrointestinal.
Diarrhea was the most frequent AE
in the nintedanib groups compared to the
placebo groups, and was reported in 61.5%
v. 18.6% of participants in INPULSIS-1 and
63.2% v. 18.3% of participants in INPULSIS-
2. Most cases were mild to moderate in
intensity (93.7% in INPULSIS-1 and 95.2%
in INPULSIS-2). In both trials, about 4.5% of
people who used nintedanib discontinued
treatment due to diarrhea (n=28 of 638).

June 2, 2014

InterMune has issued results of a phase
III trial of pirfenidone in patients with
idiopathic pulmonary fibrosis (IPF). The
mean decline from baseline to week 52
in FVC volume, a measurement of lung
capacity, was 235mL in the pirfenidone
group and 428mL in the placebo group
(absolute difference, 193mL; relative
difference, 45.1%; p<0.0001). The slope of
decline in FVC through week 52 was 122mL/yr
in the pirfenidone group and 262mL/yr in
the placebo group (absolute difference,
140mL/yr; relative difference, 53.5%;
p<0.0001). Treatment with pirfenidone was
associated with fewer deaths, although
the study was not powered for and did not
reach statistical significance on mortality.
A pre-specified analysis of the pooled
population from ASCEND and the two
phase III CAPACITY studies showed the
risk of all-cause mortality was reduced by
48% at week 52 in the pirfenidone group
compared to the placebo group (Hazard
Ratio [HR] 0.52, log rank p=0.0107). In the
trial, treatment with pirfenidone showed a
favorable safety profile and was generally
well-tolerated. InterMune intends to
resubmit the pirfenidone NDA to the FDA.

March 10, 2014

InterMune released results of a phase
III trial of pirfenidone in patients with
idiopathic pulmonary fibrosis (IPF). The
multinational, randomized, double-blind,
placebo-controlled phase III trial enrolled 555
subjects randomly assigned 1:1 to receive
oral pirfenidone (2403mg/day) or placebo
and were enrolled at 127 centers in the U.S.,
Australia, Brazil, Croatia, Israel, Mexico, New
Zealand, Peru and Singapore. Pirfenidone
significantly reduced IPF disease progression
as measured by change in percent predicted
forced vital capacity (FVC) from baseline to
week 52 (p<0.000001). At week 52, 16.5%
of patients in the pirfenidone group experienced
an FVC decline of 10% or more or
death, compared with 31.8% in the placebo
group, representing a 47.9% reduction in the
proportion of patients who experienced a
meaningful change in FVC or death. Additionally,
at week 52 the data demonstrated 22.7%
of patients in the pirfenidone group experienced
no decline in FVC, compared with 9.7%
in the placebo group, representing a 132.5%
increase in the proportion of patients whose
FVC did not decrease between baseline and
week 52. Pirfenidone reduced the risk of death
or disease progression by 43% compared
to placebo (Hazard Ratio [HR]=0.57; 95%
confidence interval, 0.43-0.77; p=0.0001). Significant
treatment effects were demonstrated
on both of the key secondary endpoints of
six-minute walk test distance (6MWD) change
(p=0.0360) and progression-free survival (PFS)
(p=0.0001). Pirfenidone reduced by 27.5%
the proportion of patients who experienced
a decline in 6MWD of 50 meters or greater
(p=0.0360). InterMune is preparing a resubmission
of an NDA for pirfenidone to the FDA
by the early third quarter of this year.

March 3, 2014

InterMune reported results of a phase III
trial of pirfenidone in patients with idiopathic
pulmonary fibrosis (IPF). The multinational, randomized,
double-blind, placebo-controlled trial
enrolled 555 patients assigned 1:1 to receive
oral pirfenidone (2403mg/day) or placebo and
were enrolled at 127 centers in the U.S., Australia,
Brazil, Croatia, Israel, Mexico, New Zealand,
Peru and Singapore. Pirfenidone significantly
reduced IPF disease progression as measured
by change in percent predicted forced vital
capacity (FVC) from baseline to week 52 (rank
ANCOVA p<0.000001). At week 52, 16.5% of patients
in the pirfenidone group experienced an
FVC decline of 10% or more or death, compared
with 31.8% in the placebo group, representing
a 47.9% reduction in the proportion of patients
who experienced a meaningful change in FVC
or death. Additionally, at week 52, 22.7% of
patients in the pirfenidone group experienced
no decline in FVC, compared with 9.7% in the
placebo group, representing a 132.5% increase
in the proportion of patients whose FVC did not
decrease between baseline and week 52. Inter-
Mune is preparing a resubmission of its NDA for
pirfenidone to the FDA.

June 3, 2013

Promedior reported results a phase Ib trial of PRM-151 for the treatment of idiopathic pulmonary fibrosis (IPF). This randomized, double-blind, placebo-controlled study enrolled 21 subjects with IPF. Subjects received PRM-151 doses of 1mg/kg, 5mg/kg or 10mg/kg, or placebo, administered intravenously on days 1, 3, 5, 8 and 15. Subjects were followed for 57 days after receiving their first dose. Subjects who received PRM-151 showed a measurable increase in lung function from baseline, as quantified by percent predicted FVC at eight weeks. The percent predicted FVC for patients dosed with PRM-151 showed a mean increase from baseline of 2.4% at eight weeks; in contrast, patients who received placebo had a mean 1.5% decrease from baseline. Percent predicted FVC increased by 10% from baseline in three of the 14 patients receiving PRM-151, and by 5% in three additional patients receiving PRM-151. In addition, the mean total distance walked in the six-minute walk test increased by 8 meters in PRM-151 treated patients and declined by 10.5 meters in placebo patients. The mean DLCO decreased by 1.79% in PRM-151 treated patients and by 2.33% from baseline in placebo patients. All doses of the drug were well tolerated. Promedior plans to initiate clinical development of PRM-151 in myelofibrosis.

May 23, 2011

Promedior reported results from a phase I trial of PRM-151 for idiopathic pulmonary fibrosis (IPF). This randomized double blind, placebo controlled study initially enrolled 26 healthy subjects who received single intravenous doses of PRM-151 from 0.1mg/kg to 20mg/kg. After completion of dosing of the healthy subjects, three subjects with IPF were administered a single dose of 10mg/kg intravenously. Single doses of PRM-151 up to 20mg/kg were safe and well tolerated in both populations. Analysis of efficacy biomarkers comparing the healthy versus IPF subjects showed a 50% reduction of CD45+/collagen-1+ fibrocytes within peripheral blood of all IPF subjects at 24 hours, and fibrocytes remained suppressed for up to 21 days in the majority of subjects. Analysis also indicated that elevated serum IL-6 levels observed at baseline in the IPF subjects decreased up to 50% (P<0.05) when measured 48 hours after PRM-151 dosing.

February 9, 2009

InterMune reported positive results from two phase III trials of pirfenidone for the treatment of idiopathic pulmonary fibrosis. The primary endpoint of both studies was change in forced vital capacity (FVC), a measure of lung function, after 72 weeks of treatment. The first trial was dubbed CAPACITY 1 and randomized 344 subjects to receive three capsules of pirfenidone (total daily dose 2403 mg) or placebo thrice daily for 60 weeks. The primary endpoint in this study was not met (p≡0.501), but supportive evidence of a pirfenidone treatment effect was observed on a number of measures. The least squares (LS) mean change in percent predicted FVC at Week 72 was -6.5% and -7.2% for pirfenidone and placebo, respectively, representing a relative reduction of 10%. Pirfenidone treatment was associated with a statistically significant effect in the pre-specified secondary endpoint of Six-Minute Walk Test distance (p≡0.001) when compared to placebo. The second trial was dubbed CAPACITY 2 and randomized 435 subjects to receive three capsules of pirfenidone (a total daily dose of either 2403 mg or 1197 mg) or placebo thrice daily for 60 weeks. The primary endpoint of change in percent predicted FVC at Week 72 was met with statistical significance (p≡0.001). The LS mean change in percent predicted FVC at Week 72 was -6.5% and -9.6% in the pirfenidone and placebo groups, respectively, representing a relative reduction of 32%. Pirfenidone treatment was also reached statistical significance on the pre-specified secondary endpoints of progression free survival (p≡0.023) and Categorical Change in FVC (p≡ 0.001) when compared to placebo. Pirfenidone was safe and generally well tolerated in both studies. Based on the results, InterMune is preparing for regulatory approvals in the US and EU.

June 4, 2007

Gilead issued positive results from a phase III trial of aztreonam lysine for the treatment of cystic fibrosis and concurrent pulmonary Pseudomonas aeruginosa infection. This double-blinded randomized trial, dubbed AIRCF-1 enrolled 164 subjects who received aztreonam lysine (75 mg) or placebo three times daily for 28 days. The primary endpoint was change from baseline in respiratory symptoms, as assessed by the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Results revealed a significant improvement in the CFQ-R, with a mean change from baseline of 9.7 points compared to placebo (p less than 0.001). Respiratory function, as measured by improvement of forced expiratory volume in one second (FEV1) was also improved. At day 28 subjects in the aztreonam lysine group with a mean change from baseline of 10.3% versus placebo (p less than 0.001). Based on positive phase III results, Gilead plans to submit a NDA to the FDA in the second half of 2007.

Pipex released positive results from a phase I/II trial of Coprexa for the treatment of refractory Idiopathic Pulmonary Fibrosis (IPF). This open-label trial enrolled 20 subjects with IPF and evidence of disease progression despite treatment with prednisone +/- cytotoxic therapy. Subjects received Coprexa (20mg) orally twice a day with meals plus 20-40mg orally at bedtime, for one year. Through-out the treatment duration subjects were monitored for adverse events, change in pulmonary function as measured by percent predicted forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLco) and walk distance (six minute walk test). Treatment was generally well tolerated. FVC was stable in 60% of subjects, improved in 10% of subjects and worsened in 30% of subjects. DLco remained stable in 75% of the subjects and improved in 5%. DLco fell in 20% of subjects. At 1 year, the 6 minute walk test improved from 611 feet to 735 feet. Based on the results, Pipex plans to initiate an additional twelve month, multi-center, randomized, double-blind, placebo-controlled trial of Coprexa later in 2007.

December 5, 2005

Actelion reported negative results of their phase III BUILD-1 trial of Tracleer (bosentan) for the treatment of idiopathic pulmonary fibrosis (IPF). Trial data failed to demonstrate a significant improvement in distance walked in a 6 minute walk exercise test vs. placebo, the trial's primary endpoint. Secondary data were also non-significant, but did yield a positive trend in the combined incidence of death or treatment failure (worsening of pulmonary function tests or acute IPF decompensation) at 12 months (22.5% for bosentan, vs. 36.1% for placebo; p=0.076). This randomized, double-blind, placebo-controlled, multi-center study enrolled 158 patients, who were treated with the drug or placebo for 12 months. Based on these results, the company announced plans to investigate the drug's ability to reduce mortality in an additional trial.

September 3, 2002

The preliminary results of InterMune's phase III clinical trial of Actimmune (interferon gamma-1b) injection for the treatment of idiopathic pulmonary fibrosis (IPF) showed that although the primary endpoint was not met, there was a significant survival benefit in certain subgroups. 330 subjects with IPF were randomized into two groups (placebo or 200 micrograms of Actimmune injected subcutaneously three times per week), with a mean treatment period of 60 weeks. The primary endpoint - progression free survival time - was not achieved, but there was a trend in favor of the Actimmune-treated subjects, demonstrating a 10% relative reduction in the rate of progression-free survival compared to placebo. In addition, there was a 70% decrease in mortality for the Actimmune-treated subjects with mild to moderate IPF, demonstrating a statistically significant survival benefit for that group compared to placebo.